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Crystal form, preparation method and application of prostaglandin analogue

一种晶型、药物的技术，应用在化学制药领域，能够解决前列腺素类化合物稳定性差等问题

Active Publication Date: 2013-07-10
SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Generally, prostaglandin compounds have poor stability and need to be stored below -20°C. From the perspective of compound stability and purity, there is an urgent need in this field to obtain a stable crystal form of compound I

Method used

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  • Crystal form, preparation method and application of prostaglandin analogue
  • Crystal form, preparation method and application of prostaglandin analogue
  • Crystal form, preparation method and application of prostaglandin analogue

Examples

Experimental program
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preparation example Construction

[0054] The preparation method of compound I crystal form B

[0055] The present invention also provides a preparation method of the crystal form B of the compound represented by formula I.

[0056] In one embodiment provided by the present invention, the preparation method of the crystal form B of the compound of formula I comprises the following steps:

[0057] (1) mixing the crude product of the compound shown in formula I with solvent 1 to obtain solution 1; said solvent 1 is selected from the group consisting of acetone, isopropanol, n-propanol, tetrahydrofuran, or a mixture thereof,

[0058] (2) Cool down and stir the solution 1 to precipitate the crystal form B of the compound of formula I.

[0059] In step (1), the mixing should be performed below the boiling point of solvent 1, preferably at 20-60°C, more preferably at 40-50°C.

[0060] In step (1), the mixing ratio (weight to volume ratio) of the crude product of the compound represented by formula I and solvent 1 i...

Embodiment 1

[0099] Preparation of crude compound I

[0100] With reference to the preparation method reported in the document J.Org.Chern.2004, 69, 1890-1902, (1R, 2R, 3aS, 9aS)-2,3,3a,4,9,9a-hexahydro-1-[( 3S)-3-Hydroxyoctyl]-1H-phenyl[f]indene-2,5-diol was used as the starting material, and 41 g of crude compound I was obtained without purification.

Embodiment 4

[0106] Preparation of compound I crystal form B

[0107] In a 25ml eggplant-shaped bottle, add the crude compound I obtained in Example 1 (1.0g) and acetone (1.5ml), heat up to 40°C and dissolve to form a homogeneous solution, then slowly cool down to 5°C and stir for 10h, filter, 5 It was washed 2-3 times with acetone at °C and dried to obtain 0.91 g of crystalline solid. X-ray powder diffraction pattern and figure 1 Consistent, Differential Scanning Calorimetry (DSC) chart with figure 2 Consistent, the infrared spectrum and image 3 Consistent, HPLC purity 99.90%. Organic residue: acetone 0.05% (mass yield: 91%)

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Abstract

The invention discloses a crystal form B, a preparation method and application of a compound with a structural formula shown as a formula I. An X-ray powder diffraction graph (XRPD) of the crystal form B shows characteristic peaks at the following 2 theta angles: 2.9+ / - 0.2 DEG, 6.5+ / -0.2 DEG, 12.6 + / -0.2 DEG, 13.1 + / -0.2 DEG and 20.6 + / -0.2 DEG.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular to a crystal form of a prostaglandin analogue and a preparation method and use thereof. Background technique [0002] Treprostinil (UT15, Treprostinil) is a new class of drugs for the treatment of pulmonary arterial hypertension. Its structure is shown in formula IV: [0003] [0004] Pulmonary arterial hypertension (PAH) is a disease characterized by vasospasm, intimal hyperplasia and remodeling of pulmonary arterioles. Vascular proliferation and remodeling of pulmonary arterioles lead to a progressive increase in pulmonary vascular resistance, eventually leading to right ventricular failure and death. [0005] Epoprostenol (Flolan) is the first prostacyclin drug approved by the US Food and Drug Administration (FDA) for the treatment of PAH. The half-life of epoprostenol in the circulation is about 3 to 5 minutes, and continuous intravenous administration is required, and it ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/72C07C51/347A61K31/191A61P9/12
CPCC07B2200/13C07C59/66C07C2603/14A61P11/00A61P9/12C07C59/72
Inventor 唐志军刘毓彬何兵明杨君季晓铭
Owner SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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